Zolgensma (onasemnogene abeparvovec-xioi), previously known as AVXS-101, is a gene therapy initially developed by AveXis, now part of Novartis, which is further developing and marketing the treatment. It targets the underlying genetic cause of spinal muscular atrophy (SMA).

Zolgensma was approved by the U.S. Food and Drug Administration (FDA) in 2019 to treat all types of SMA in newborns and toddlers up to age 2 through a single intravenous (IV) administration. This approval makes Zolgensma the second disease-modifying treatment for SMA, and its first gene therapy. 

The Japanese Ministry of Health, Labour, and Welfare approved Zolgensma in March 2020 for the treatment of SMA in patients under two.

Zolgensma was also granted conditional approval by the European Commission in May 2020 for patients with type 1 SMA or three or fewer SMN2 gene copies who weigh 21 kg (around 46lbs) or less.

Health Canada approved Zolgensma for the treatment of patients with three or fewer copies of the SMN2 gene or infantile-onset SMA in December 2020.

How does Zolgensma work?

SMA is caused by a mutation in the SMN1 gene, which encodes for the SMN protein that motor neurons — the nerve cells that control muscle contraction — need to survive. The mutation prevents this gene from producing a functional SMN protein.

Zolgensma is designed to deliver a working copy of the SMN1 gene to motor neurons in SMA patients.

Zolgensma comprises the shell (capsid) of a genetically engineered virus, the so-called adeno-associated virus (AAV) 9, which carries a normal copy of the SMN1 gene to its target motor neurons. Once the SMN1 gene (called a transgene because it comes from an external source) reaches patients’ cells, it allows those cells to produce the SMN protein.

The SMN1 transgene in Zolgensma consists of double-stranded DNA, meaning that it takes the same form as natural genes and can be activated more quickly, to be a faster and more efficient therapy. Zolgensma also includes the genetic instructions to activate the transgene, so that SMN protein production is continuous and sustainable.

Zolgensma in clinical trials

A Phase 1 open-label clinical trial, called START (NCT02122952), evaluated the safety, tolerability, and efficacy of Zolgensma in 15 infants, up to 6 months old, with SMA type 1 (the disease’s most common and severe form). It assessed Zolgensma, given at a low (three infants) or high dose (12 infants), as a one-time injection into a vein in the arm or leg.

Study results published at a two-year cutoff date, when all were at least 20 months old, found none required permanent mechanical ventilation to assist with breathing. In comparison, only 8% of patients in the disease’s natural (untreated) history survive to the same age without permanent ventilation. Seven children in the high-dose group were completely independent of ventilatory assistance. A total of 11 toddlers had achieved and retained the ability to swallow independently, and four were able to feed themselves by mouth. 

Among the 12 infants who received Zolgensma at a high dose, 11 were able to achieve head control. Nine were able to roll at least 180 degrees, from the back to both the left and the right side. Eleven of the children were able to sit unaided for at least five seconds, 10 for at least 10 seconds, and nine for at least 30 seconds. Again, these were achievements normally never seen in babies with SMA type 1 in the absence of disease-modifying treatment.

Overall motor skills were assessed using the CHOP-INTEND score, which is based on a questionnaire that contains 16 items scored 0 to 4. The total score ranges from 0 to 64; higher scores indicate better motor skills.

In the group given the high dose of Zolgensma, CHOP-INTEND scores increased by 9.8 points at one month following treatment, and by 15.4 points at three months. Of these 12 children, 11 attained and sustained a score of more than 40 points. At the study’s 2017 cutoff, the children had a mean increase of 24.6 points. The three treated at low dose had a mean increase of 7.7 points.

At a follow-up analysis at 24 months post-treatment, all 15 patients were still alive and did not require permanent ventilation. Two more children in the high-dose group (11 of 12) were able to sit unaided for 30 seconds or more. A total of 11 patients in this group reached a CHOP-INTEND score equal to or greater than 40, and 10 achieved scores of 50 or higher.

These 15 children are now enrolled in a long-term safety study (NCT03421977), where they are being monitored annually for up to 15 years (through December 2033).

A Phase 3 trial, called STR1VE (NCT03306277), included 22 infants with SMA type 1 to further assess the treatment’s safety and effectiveness.

Results, in the 20 patients who completed the trial, found their mean CHOP-INTEND score increased by an average of 6.9 points one month after treatment. Two months later, scores had improved by 11.7 points. When the trial ended in November 2019, these 20 children also did not need ventilation, and five of the six patients who reached 18 months of age by study end were able to sit independently for 30 seconds.

A similar trial in Europe, called STR1VE-EU (NCT03461289) concluded in September 2020. Interim data from the trial as of December 2019 was presented at the 2020 World Muscle Society Virtual Conference and showed that 21 of the 33 patients were able to achieve developmental milestones not usually seen in children with SMA. One patient was able to crawl and stand and walk with assistance, six were able to sit on their own for 10 seconds or more, eight were able to roll from their back to their side, and 20 patients gained the ability to control their head. One child did have a severe adverse reaction during the trial which lead to their death but it was considered to be unrelated to treatment with Zolgensma after an autopsy. 

An Asia-Pacific version of the trial, called STR1VE-AP (NCT03837184) completed recruitment of two eligible infants at sites in Japan, Taiwan, and South Korea. The study is ongoing with results expected in June 2021.

Another clinical trial, placed on an FDA-ordered clinical hold in October 2019, is testing different doses of Zolgensma in children with SMA type 2, whose symptoms usually appear between 7 and 18 months old. This Phase 1/2 trial, called STRONG (NCT03381729), is assessing the safety and tolerability of two doses of Zolgensma — delivered as a single intrathecal (spinal cord) infusion — in 32 children, 6 months to 5 years old. Patients are divided into two groups (younger or older than age 2) at the time of dosing. Three patients received the lowest dose, 25 received the medium dose, and four received the highest dose level.

STRONG is on a partial clinical hold while the FDA investigates preclinical findings of inflammation in primates given Zolgensma by spinal infusion. Similar inflammation has not been seen in children treated to date in the trial.

Interim results of patients who were already given Zolgensma before the clinical hold showed significant improvements in the Hammersmith Functional Motor Scale-Expanded (HFMSE) scores and no new safety concerns between what is seen in the IV administration trials. The 12 children in the age 2 to 5 group who received the middle dose of Zolgensma achieved an average increase of six points in the HFMSE score, twice what was deemed to be a clinical improvement. The improvement in score is in contrast to the decrease in score that children with SMA usually display. Novartis announced that they will also be starting a new intrathecal injection trial in older patients with SMA. The new trial was requested by the FDA to aid in the potential approval of intrathecal administration of Zolgensma for older patients.

A Phase 3 clinical trial (NCT03505099), called SPR1NT, is investigating Zolgensma in presymptomatic infants thought to have SMA type 1, type 2, or type 3, and ages 6 weeks or younger. Interim results in 29 patients were promising, with several of the children being able to sit unaided, and others being able to stand with assistance as they mature. The trial is no longer recruiting and is expected to be complete in July 2021.

Patients that have completed a clinical trial of Zolgensma will also be rolled into a long-term follow-up study (NCT04042025) where they will be monitored for up to 15 years after receiving Zolgensma. The trial is expected to be completed in December of 2035.

Other information

Zolgensma was approved by the FDA, under a priority review, on May 24, 2019, as a one-time IV treatment for people with any type of SMA up to age 2. 

Its U.S. list price is $2.125 million for a single treatment, and Novartis allows for installment payments of $425,000 over five years.

Novartis opened a managed access program (MAP) — which some refer to as a lottery — offering up to 100 treatments with Zolgensma each year to eligible young SMA children under age 2 outside the U.S. This MAP started in 2020.

Zolgensma’s use can increase serum aminotransferase (a liver enzyme) levels to a degree that is considered a serious adverse event. Rises in these levels, however, can be controlled with prednisolone, a glucocorticoid. An article found that treatment with Zolgensma can also lead to a rare condition called thrombotic microangiopathy characterized by the destruction of red blood cells, low levels of platelets, and blood clots in small blood vessels throughout the body. All three cases (roughly 0.6% of patients who had received Zolgensma at the time) were able to be resolved through treatment.

Zolgensma is expected to be a one-time, life-long treatment, although enough time has not yet passed from its first clinical trials to know that with certainty. But it can only be used once, for now, because treated patients develop antibodies — an immune system response — against the viral vector that serves as a transport agent, and these antibodies lower Zolgensma’s effectiveness.

This is a problem shared by gene therapies in development for other diseases that also use a viral vector.


Last updated: Jan. 3, 2021


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